Carriers of the fragile X (FMR1) premutation have been shown to exhibit mild cognitive impairments and increased risk for psychiatric problems. Furthermore, they are at risk for developing a neurodegenerative disease, fragile X-associated tremor ataxia syndrome (FXTAS), characterized by neurological manifestations of progressive gait ataxia, intention tremor, Parkinsonism, dementia, autonomic dysfunction, and peripheral neuropathy. Neuropathological features of FXTAS include whole brain atrophy, ventricular enlargement, white matter disease, and neuronal and astrocytic intranuclear inclusion formation and neuropsychiatric symptoms include depression, anxiety, and executive dysfunction. The hypothesized molecular genetic pathogenic mechanism of FXTAS is toxic gain-of-function of FMR1 mRNA. The disease has a variable and age-related penetrance, affecting 75% of male premutation carriers by the eighth decade of life. While the features of FXTAS have been well-described, it is not known why some carriers become affected and others do not, and the variable rate of progression and risk factors associated with disease onset are poorly understood. In the first 5 years of this program of research (Limbic System Function in Carriers of the Fragile X Premutation), alongside other collaborative studies at our center, we have demonstrated that abnormal elevation of FMR1 mRNA is associated with reduced hippocampus, amygdala, and frontal lobe function, which in turn are correlated with psychological symptoms and social deficits, impaired memory recall and working memory in male premutation carriers at risk for FXTAS. Our other studies have shown brain white matter deterioration with age, reduced brain stem and increased ventricular volume, and high rates of mood and anxiety disorders in adult carriers without FXTAS compared to controls with normal FMR1 alleles. This work has provided important clues about potential genetic, brain and neuropsychological risk factors for disease progression, however no prospective longitudinal studies have been completed that provide critical data required to identify risk or protective factors for FXTAS. For the current project, we will examine the trajectory of key neuropsychological and neurological factors in adult male carriers of the FMR1 premutation between the ages of 40 and 69, in comparison to male controls without the premutation, using a longitudinal design. We will examine how several FMR1 molecular measures play a role in mediating the rate of progression of these key factors. The results of the study will provide critical information about the early markers of neurodegeneration that will aid in identification o patients most in need of preventive care and treatment as these interventions become available, and it may identify important measures to track response to interventions in the future.